Neurotoxicity of Reactive Astrocyte-secreted Lipids in Neurodegenerative Disease

反应性星形胶质细胞分泌的脂质在神经退行性疾病中的神经毒性

基本信息

批准号：
10576374
负责人：
Shane Liddelow
金额：
$ 54.05万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576374
关键词：
Acute Address Affect Aging Apoptosis Astrocytes Automobile Driving Autopsy Axon BBC3 gene Blindness CASP3 gene CRISPR screen Cell Death Cell Death Induction Cells Central Nervous System Cessation of life Characteristics Chronic Development Disease Electrophysiology (science)Enzymes Excision Eye Eye Injuries Eye diseases Future Genes Genetic Glaucoma Goals Health Human Immune response In Vitro Individual Infection Inflammation Injury Knock-out Knockout Mice Lipids Maintenance Maps Mediating Mediator Modeling Mus Nerve Crush Nerve Degeneration Neurodegenerative Disorders Neurons Neurotoxins Nonesterified Fatty Acids Optic Nerve Optic Nerve Injuries Pathologic Pathway interactions Patients Peripheral Phenotype Phosphotransferases Physiologic Intraocular Pressure Physiological Predisposition Production Proteins Reporting Research Resistance Retina Retinal Degeneration Retinal Ganglion Cells Rodent Model Role Stress Synapses Testing Thalamic structure Time Tissues Toxic effect Vision Visual Acuity Western Blotting Work activating transcription factor 3 axon injury biological adaptation to stress cell type combinatorial endoplasmic reticulum stress improved in vivo in vivo Model innovation insight ischemic injury knockout animal mouse model neuron loss neuronal cell body neurotoxic neurotoxicity neurotransmission neurotrophic factor new therapeutic target novel novel strategies pharmacologic preservation prevent protein activation protein kinase R regeneration following injury response to injury saturated fat tool virtual reality system

项目摘要

PROJECT SUMMARY Glaucoma is a neurodegenerative disease of aging that features the death of retinal ganglion cell neurons (RGCs) in the retina, often as a result of prolonged increases in intraocular pressure. This cell death leads to a decrease in visual acuity and ultimately blindness. While glial and immune responses have been associated with glaucoma, little understood about their potential causative role in loss of vision. Reactive astrocytes are increasingly shown to appear well before traditional pathological readouts of a wide range of neurodegenerative diseases, including glaucoma. One subset of reactive astrocytes reported by us and others as putatively neurotoxic. These neurotoxic reactive astrocytes are present in regions of neurodegeneration in human postmortem tissue from patients with multiple diseases of aging, as well as in the retina following acute injury to RGC axons and in a chronic retinal degeneration in a bead occlusion model of glaucoma. Preventing formation of neurotoxic reactive astrocytes prevents death of neurons, and spared neurons are electrophysiologically functional and thus still have potential value for regeneration following injury and in disease. We now report that these reactive astrocytes secrete a potent neurotoxic lipid, specifically long-chain free fatty acids, that induce death of neurons, both in vitro and in vivo. Block of the enzyme involved in production of toxic lipids, Elovl1, in astrocytes preserves neuron numbers. Together, these findings highlight a subset of reactive astrocytes as drivers of RGC death in a chronic neurodegenerative disease of the eye. Here we will investigate the role of reactive astrocyte-derived toxic lipids to determine the timing and mechanism of reactive astrocytes in driving death of RGC somas in the retina, during acute and chronic injury to the eye. We will focus on three broad research questions: is the PERK-ATF3 pathway required to drive neuron cell death by astrocyte toxic lipids? Does blocking neurotoxic reactive astrocytes preserve neuronal function and visual acuity in a mouse model of glaucoma? And what is the requirement for neuronal susceptibility prior to astrocyte-induced cell death? We will determine maintenance of optic nerve axons using a mouse model deficient for neurotoxic lipids released by reactive astrocytes in combination with investigating changes in visual acuity in glaucomatous mice using both wildtype and toxic lipid-deficient mice to determine if targeting reactive astrocytes can preserve vision. We will also investigate individual components of the PERK-ATF3 mediated lipoapoptosis pathway – a putative mechanism by which reactive astrocyte secreted toxic lipids drive death of neurons. This proposal will investigate a novel approach to maintain vision during glaucoma. It will provide for the first time a connection between astrocyte reactivity, RGC health, visual acuity, and thalamic synaptic connections.

项目摘要青光眼是一种衰老的神经退行性疾病，具有残留神经节细胞神经元死亡（RGC）在视网膜中，通常是由于眼内压力增加而导致的。这种细胞死亡导致视力降低并最终失明。虽然神经胶质和免疫反应与青光眼，对它们在视力丧失中的潜在结构作用几乎没有理解。反应性星形胶质细胞是在广泛的神经退行性范围的传统病理读数之前，越来越表现出很好的表现疾病，包括青光眼。我们和其他人报告的一个反应性星形胶质细胞的一部分神经毒性。这些神经毒性的反应性星形胶质细胞存在于人类神经退行性的区域急性损伤后，来自多种衰老疾病的患者以及视网膜中的死后组织在青光眼的珠子闭塞模型中，RGC轴突和慢性视网膜变性。防止形成神经毒性的反应性星形胶质细胞可预防神经元死亡，而保留的神经元在电生理上是功能性，因此在受伤和疾病后仍具有再生的潜在价值。现在，我们报告这些反应性星形胶质细胞分泌潜在的神经毒性脂质，特别是长链脂肪酸，会在体外和体内诱导神经元死亡。涉及有毒产生的酶的块脂质，Elovl1，在星形胶质细胞中保存神经元数。这些发现一起突出了一个反应性的子集星形胶质细胞是眼睛慢性神经退行性疾病中RGC死亡的驱动因素。在这里我们将调查反应性星形胶质细胞衍生的有毒脂质的作用在确定反应性星形胶质细胞的时间和机理在视网膜中RGC Somas的死亡时，眼睛急性和慢性损伤。我们将专注于三个广泛的研究问题：是由星形胶质细胞驱动神经元细胞死亡所需的PERK-ATF3途径有毒脂质？阻断神经毒性反应性星形胶质细胞可保留神经元功能和视力在青光眼的小鼠模型中？以及对神经元易感性之前的要求是什么星形胶质细胞引起的细胞死亡？我们将使用鼠标模型确定视神经轴突的维护反应性星形胶质细胞释放出的神经毒性脂质不足，并研究视觉变化使用野生型和有毒脂质缺陷型小鼠的青光眼小鼠的敏锐度，以确定是否靶向反应性星形胶质细胞可以保持视力。我们还将研究PERK-ATF3介导的单个组件脂肪凋亡途径 - 一种推定的机制，反应性星形胶质细胞分泌有毒脂质驱动死亡神经元。该建议将研究一种新的方法，以维持青光眼期间的视力。它将提供第一个时间是星形胶质细胞反应性，RGC健康，视力和丘脑突触连接之间的联系。